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Cell Rep. 2014 Nov 20;9(4):1292-305. doi: 10.1016/j.celrep.2014.10.044. Epub 2014 Nov 13.

Uncoupling Malt1 threshold function from paracaspase activity results in destructive autoimmune inflammation.

Author information

1
Institut für Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technische Universität München, 81675 München, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
2
Institut für Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technische Universität München, 81675 München, Germany.
3
Department of Neurology, Klinikum rechts der Isar, Technische Universität München, 81675 München, Germany.
4
Institute for Immunology, Ludwig-Maximilians-Universität München, Goethestraße 31, 80336 München, Germany; Helmholtz Zentrum München, Institute of Molecular Immunology, 81377 München, Germany.
5
Institute of Pathology, Julius-Maximilians-Universität Würzburg and Comprehensive Cancer Center Main-Franken, 97080 Würzburg, Germany.
6
Institut für Pathologie, Universitätsklinikum Heidelberg, 69120 Heidelberg, Germany.
7
Helmholtz Zentrum München - German Research Center for Environmental Health, Institute of Experimental Genetics, 85764 Neuherberg, Germany.
8
Helmholtz Zentrum München - German Research Center for Environmental Health, Institute of Experimental Genetics, 85764 Neuherberg, Germany; Institute of Experimental Genetics, Technische Universität München-Weihenstephan, 85350 Freising-Weihenstephan, Germany.
9
Helmholtz Zentrum München - German Research Center for Environmental Health, Institute of Developmental Genetics, 85764 Neuherberg, Germany; Munich Cluster for Systems Neurology (SyNergy), 81675 München, Germany; Technische Universität München-Weihenstephan, Institute of Developmental Genetics, c/o Helmholtz Zentrum München, 85764 Neuherberg, Germany; Deutsches Zentrum für Neurodegenerative Erkrankungen e.V. (DZNE), Standort München, 80336 München, Germany.
10
Institute of Virology, Technische Universität München/Helmholtz Zentrum München, 81675 München, Germany.
11
Department of Neurology, Klinikum rechts der Isar, Technische Universität München, 81675 München, Germany; Munich Cluster for Systems Neurology (SyNergy), 81675 München, Germany.
12
Institut für Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technische Universität München, 81675 München, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; German Center for Infection Research (DZIF), partner site Munich, 81675 München, Germany. Electronic address: jruland@lrz.tum.de.

Abstract

The paracaspase Malt1 is a central regulator of antigen receptor signaling that is frequently mutated in human lymphoma. As a scaffold, it assembles protein complexes for NF-κB activation, and its proteolytic domain cleaves negative NF-κB regulators for signal enforcement. Still, the physiological functions of Malt1-protease are unknown. We demonstrate that targeted Malt1-paracaspase inactivation induces a lethal inflammatory syndrome with lymphocyte-dependent neurodegeneration in vivo. Paracaspase activity is essential for regulatory T cell (Treg) and innate-like B cell development, but it is largely dispensable for overcoming Malt1-dependent thresholds for lymphocyte activation. In addition to NF-κB inhibitors, Malt1 cleaves an entire set of mRNA stability regulators, including Roquin-1, Roquin-2, and Regnase-1, and paracaspase inactivation results in excessive interferon gamma (IFNγ) production by effector lymphocytes that drive pathology. Together, our results reveal distinct threshold and modulatory functions of Malt1 that differentially control lymphocyte differentiation and activation pathways and demonstrate that selective paracaspase blockage skews systemic immunity toward destructive autoinflammation.

PMID:
25456129
DOI:
10.1016/j.celrep.2014.10.044
[Indexed for MEDLINE]
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